ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2489+4A>C (rs1064793905)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478943 SCV000567313 pathogenic not provided 2015-07-24 criteria provided, single submitter clinical testing The c.2489+4 A>C variant has been reported previously in association with ARVC (Bhuiyan et al., 2009;Cox et al., 2011; van der Smagt et al., 2012; Te Riele et al., 2013). The c.2489+4 A>C substitution has beenreported in four Dutch families with ARVC with varying degrees of severity, ranging from severe diseaseto non-penetrance (van der Smagt et al., 2012). The authors proposed that this variant is a Dutch foundervariant and that these families likely share a common ancestor. RT-PCR and sequencing demonstratedthat c.2489+4 A>C causes skipping of exon 12, leading to a frameshift and the introduction of a stop codonin the 3' untranslated region. The resulting protein product is predicted to be 15 amino acids shorter thanthe wild-type protein (van der Smagt et al., 2012). The c.2489+4 A>C substitution was absent in at least 200controls (Bhuiyan et al., 2009; Cox et al., 2011; van der Smagt et al., 2012). This substitution occurs at anucleotide position that is conserved across species. Additionally, other splice site variants in the PKP2gene, including others involving the same splice donor site (c.2489+1 G>A, c.2489+1 G>T), have beenreported in HGMD in association with ARVC (Stenson P et al., 2014). Furthermore, the c.2489+4 A>Cvariant was not observed in approximately 6,500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret the c.2489+4 A>C variant as pathogenic.

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